This invention relates to the corticotropin releasing hormone (CRH) compounds 4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine and (3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl)-(1-ethyl-propyl)-a mine and the use thereof in treating heart failure.
The impact of heart failure continues to increase. Approximately three percent of the adult U.S. population (three to four million patients) have heart failure. With a steadily aging population, four hundred thousand individuals experience new onset heart failure each year, with a five year mortality rate approaching fifty percent. In 1991, alone, 2,280,445 patients were discharged from non-federal U.S. hospitals with a diagnosis of heart failure.
Congestive heart failure, regardless of its etiology, is characterized by a weakness of the myocardial tissue of the left and/or right ventricles of the heart to pump and circulate blood into systemic and/or pulmonary circulations. It is accompanied by circulatory and neurohumoral changes which result in failure to deliver sufficient blood and oxygen supply to peripheral tissues and vital organs. If left untreated the health of a patient with congestive heart failure could deteriorate to the point where the disease would be fatal. Congestive heart failure may be expressed as shortness of breath either on exertion, at rest or paroxysmal nocturnal dyspnea.
While angiotensin converting enzyme (ACE) inhibitors have been shown to demonstrate a significant reduction in both hospitalization and mortality in congestive heart failure patients, diuretics and digoxin continue to be more highly prescribed agents most likely due to their ability to provide effective symptomatic relief. However, digoxin's use is limited because of its slow onset of action and the small difference between the maximum therapeutic and minimum toxic dose levels. Moreover, the improved survival in patients treated with ACE inhibitors occurs primarily in the initial twelve months of therapy. Thus, a truly dramatic impact on disease progression has yet to be realized.
4-(1-Ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine and (3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl)-(1-ethyl-propyl)-a mine are disclosed in International Patent Application Publication No. WO95/33,750 as having activity as a corticotropin releasing factor antagonist and, accordingly, utility in the treatment of a wide range of stress-related illnesses such as depression, anxiety, headache, irritable bowel syndrome, inflammatory diseases, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, infertility, head trauma, stroke, and stress-induced infections in humans and animals.
4-(1-Ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine and (3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl)-(1-ethyl-propyl)-a mine are also disclosed as part of a genus of compounds in International Patent Application Publication No. EP 07773023 as having utility in the treatment of a wide variety of cardiovascular or heart related diseases such as hypertension, tachycardia, congestive heart failure, stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus, and colonic hypersensitivity associated with psychopathological disturbance and stress.
Thus, although there are a variety of treatments for congestive heart failure there is a continuing need and a continuing search in this field of art for alternative therapies.